# Early Administration of N-Acetylcysteine Provides Renal and Cardiac Mitochondrial and Redox Protection, Preventing the Development of Cardio-Renal Syndrome Type IV Induced by 5/6NX

## TL;DR

Early use of N-acetylcysteine protects kidney and heart mitochondria, preventing a type of cardio-renal syndrome caused by kidney damage.

## Contribution

The study reveals early mitochondrial and redox changes in CRS-IV and shows NAC's protective role via SIRT1/3-PGC-1α pathway activation.

## Key findings

- Cardiac mitochondrial alterations and plasma cardio-renal connectors increase 10 days after CKD induction.
- NAC prevents mitochondrial and redox damage in kidneys and heart, reducing inflammation and CRS-IV.
- NAC's protection is linked to SIRT1/3-PGC-1α pathway overactivation, suggesting a novel therapeutic strategy.

## Abstract

Chronic kidney disease (CKD) cardiac impairment is manifested as cardio-renal syndrome type 4 (CRS-IV). The kidneys and heart are highly dependent on mitochondria; thus, bioenergetics and redox and biogenesis alterations are critical in CKD and heart damage. Most previous studies have focused on the advanced stage of CRS-IV, but mitochondrial impairment onset in the early stages and its pathological pathways are poorly understood. In this work, we characterized mitochondrial bioenergetics, biogenesis and redox impairment in both tissues in the early stages after CKD and analyzed their relationship with CRS-IV in a CKD model with 5/6 nephrectomy (NX). We found the first cardiac mitochondrial alterations 10 days after surgery, together with an increase in plasma cardio-renal connectors, derived from renal mitochondrial damage. Oxidative phosphorylation capacity decreased and uncoupling led to oxidative stress, inflammation, cardiac hypertrophy and ejection fraction reduction, triggering CRS-IV. N-acetylcysteine (NAC) administration prevented mitochondrial alterations in both organs and heart damage. Interestingly, the protective effects of NAC correlated with SIRT1/3-PGC-1α pathway overactivation. These results suggest that mitochondrial biogenesis induction and redox regulation protection in the early stages after renal damage serve as a strategy to prevent bioenergetic alterations in the kidneys and heart, preventing inflammation and CRS-IV development.